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Big data reveals hints of how, when and where mental disorders start
New genetic complexities emerge for schizophrenia, bipolar disorder and autism大数据揭示了精神障碍如何、何时、何地开始的线索
精神分裂症、双相情感障碍和自闭症患者出现了新的遗传复杂性
BY LAURA SANDERS 2:49PM, DECEMBER 13, 2018
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ON THE BRAIN Lab-grown brain organoids (one shown) mimic the real thing, analyses suggest. Along with other parts of a large research effort called PsychENCODE, the organoid results may offer new clues about psychiatric diseases such as schizophrenia.分析表明，实验室培育的大脑类器官(如图所示)模仿了真实的大脑。与一项名为“心理编码”(PsychENCODE)的大型研究项目的其他部分一起，这些类器官结果可能会为精神疾病(如精神分裂症)提供新的线索。
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Psychiatric disorders’ many complexities have stymied scientists looking for clear genetic culprits.精神疾病的许多复杂性阻碍了科学家寻找明确的基因致病因素 But a new giant dataset holds clues to how, when and where these brain disorders begin.
Called PsychENCODE, the project’s first large data release has revealed intricate insights into the behavior of genes and the stretches of genetic material between them in both healthy brains and those from people with schizophrenia, bipolar disorder or autism spectrum disorder.这项名为“心理编码”(PsychENCODE)的项目首次大规模数据发布，揭示了健康大脑和精神分裂症、双相情感障碍(躁郁症)或自闭症谱系障碍(autism spectrum disorder)患者大脑中基因行为和基因之间遗传物质延伸的复杂相互缠结的关系。
The results, split among 10 studies published online December 13 in Science, Science Advances and Science Translational Medicine, offer some of the most detailed looks yet at the links between these genetic elements and brain health. 12月13日发表在《科学》(Science)、《科学进展》(Science Advances)和《科学转化医学》(Science Translational Medicine)杂志网络版上的10份研究报告对这些基因元素与大脑健康之间的联系进行了迄今最详细的研究。“It’s all connected, and now we have the tools to unravel those connections,” says geneticist Thomas Lehner of the National Institute of Mental Health in Bethesda, Md., who oversaw the project but wasn’t involved in the research.
Earlier studies have pinpointed certain genes and other stretches of the genome — the genetic material that makes up cells’ instruction books — as being involved in schizophrenia, bipolar disorder and autism spectrum disorder.早期的研究已经确定某些基因和基因组的其他部分——构成细胞说明书的遗传物质——与精神分裂症、双相情感障碍和自闭症谱系障碍有关。 The new collection of work goes further, both confirming and clarifying some of these roles.新的论文集合更进一步，确认和澄清了其中的一些角色。
“This is a massive undertaking,” says neuroscientist Christine Denny of Columbia University who was not involved in the project. “It’s pretty phenomenal.”
“这是一项艰巨的任务，”哥伦比亚大学的神经系统科学家克里斯汀·丹尼(Christine Denny)说。“这是很惊人的。”
In part of the new research, neuroscientist Nenad Sestan of Yale University and colleagues looked at gene behavior as brains develop.作为这项新研究的一部分，耶鲁大学的神经科学家Nenad Sestan和他的同事们观察了大脑发育过程中的基因行为。 Samples of postmortem brains ranging from fetal stages through adulthood revealed two major points of genetic upheaval: early prenatal development and adolescence.从胎儿期到成年期的死后大脑样本揭示了基因突变的两个主要方面:早期产前发育和青春期。 Activity in groups of genes linked to psychiatric disorders suggests that these are times when important genetic behavior goes awry, the researchers say.研究人员说，与精神疾病有关的基因群的活动表明，这些时候重要的遗传行为会出错。
Similar psychENCODE analyses in rhesus macaques revealed similar developmental paths, Sestan says.Sestan说，在恒河猴身上进行的类似的心理编码分析显示了相似的发展路径。 Those comparisons also turned up some gene behavior that’s exclusive to humans (and others exclusive to macaques), differences that “may drive unique features of the diseases in humans,” he says.这些比较还发现了一些人类独有的基因行为(还有一些是猕猴独有的)，这些差异“可能驱动人类疾病的独特特征，”他说。
Other PsychENCODE projects scrutinized spots in the genome that aren’t necessarily located inside genes. Researchers linked many of these genetic hot spots, which are thought to differ in people with psychiatric diseases, to genes for the first time. That information could be used to predict a person’s risk of these psychiatric disorders from genomic makeup alone.这些信息可以用来预测一个人患这些精神疾病的风险仅从基因组构成。
Still more research uncovered important differences in how genes behave in brains from people with autism, bipolar disorder or schizophrenia. 还有更多的研究发现，自闭症、双相情感障碍或精神分裂症患者大脑中的基因表现方式存在重大差异。The researchers found that RNA, a go-between molecule that helps carry out DNA's instructions, was different in the brains of people with psychiatric disorders. Those results may ultimately lead to targeted medicines for the diseases.这些结果可能最终导致针对这些疾病的靶向药物。
Some projects also focused on how to use laboratory tools including brain organoids, clumps of neural tissue grown in dishes, to further the research.一些项目还集中在如何使用实验室工具，包括大脑器官，在培养皿中生长的神经组织块，以作进一步研究。 By comparing the gene activity of cells in brain organoids with that of cells taken from actual brains, researchers found that the two mirror each other at early stages of development. Those similarities mean that the organoids, good mimics of young brains, might be particularly useful in understanding brain disorders that start early.这些相似之处意味着，这些类器官——很好的模仿年轻大脑的器官——可能对理解早期开始的大脑疾病特别有用。
Lehner first began advocating for a group effort aimed at understanding the genetic landscape of psychiatric disorders about a decade ago雷纳在大约十年前就开始倡导组成一个团体旨在了解精神疾病遗传图景. But it wasn’t until 2015 that the National Institute of Mental Health announced plans for PsychENCODE and helped organize the 15 participating research institutions. To see the first wave of results “feels really good,” Lehner says. “I’m delighted.”
The PsychENCODE group is making progress, says Columbia University psychiatrist Jeffrey Lieberman. “But the jury is still out in terms of what it will result in,但最终的结果仍未可知” he says. “It could produce important — and if we’re lucky, game-changing — results.”“这可能产生重要的结果——如果我们幸运的话，将改变游戏规则。”
